Dimedone derivatives of dialdehydes

ABSTRACT

A novel class of dimedone derivatives of dialdehydes are useful as antimicrobial agents and fungicides. Their high activity and low toxicity make them candidates for replacements for hexachlorophene.

United States Patent 1191 Tabor [4 1 Sept. 9, 1975 [54] DIMEDONEDERIVATIVES OF DIALDEI-IYDES [76] Inventor: Robert G. Tabor, 1407 W.Tucker Blvd., Arlington, Tex. 76013 22 Filed: Nov. 8, 1973 21 Appl. N0.:413,771

OTHER PUBLICATIONS Kwan et a1., Chem. Abstracts, Vol. 61, p. 7597g(1964).

Fleury et al., Chem. Abstracts Vol. 50, p. 5466d, (1956).

Fielbuedes et al., Chem. Abstracts, Vol. 64, p. l7385g (1966).

Primary Examiner-Bernard Helfin Assistant Examiner-Norman MorgensternAttorney, Agent, or FirmAmster & Rothstein [5 7] ABSTRACT A novel classof dimedone derivatives of dialdehydes are useful as antimicrobialagents and fungicides. Their high activity and low toxicity make themcandidates for replacements for hexachlorophene.

4 Claims, N0 Drawings DIMEDONE DERIVATIVES OF DIALDEHYDES This inventionrelates to a novel class of dimedone derivatives. More particularly,this invention is concerned with the dimedone derivatives of dialdehydeswhich are found to possess antimicrobial and fungicidal activity.

The compounds of this invention exhibit strong antimicrobial activityand negligible toxicity. They are, therefore, potential replacements forhexachlorophene. They are water insoluble; thus, as doeshexachlorophene, they leave an antimicrobial residue on the skin.However, unlike hcxachlorophene they are not very lipid soluble; thus,they are not readily absorbed through the skin. In addition, thecompounds have some fungicidal activity.

The novel compounds of this invention have the following generalformula:

CH CH3 [CH3 ,CH

o 0 a s 0 H c (CH c H CH3 CH CH3 CH3 where is an integer of from I to 6and is preferably 2 to 4, most preferably 3.

The compounds can be prepared by reacting a dialdehyde such asglutaraldehyde, succinaldehyde, adi' paldehyde, malonaldehyde, orpimelaldehyde with 5,5- dimethyl-l ,3-cyclohexanedione (dimedone). Thereactants are heated at reflux for about minutes in 50 percent aqueousmethanol. The product can be formed without the need of a catalyst; abasic catalyst may even be harmful. The reaction requires four (4) molesof dimedone per mole of the dialdehyde. A slight excess of the dimedoneis desirable.

It is preferred that the dialdehydes be unsubstituted. However, certainsubstituents may be added without diminishing the effectiveness of thederivatives. It is also preferred that the 5,5-dimethyll ,3-cyclohexanedione not contain any other substituents. However. certainsubstituents may be added without diminishing the effectiveness of thecompounds of this invention.

An illustrative reaction for preparing the derivatives of this inventionis shown by the following equation:

CH3 CH3 The dimedone derivative of this invention may be applied as asolid; e.g., in an aerosol spray, or suitable diluent, such as water oran isotonic salt solution. The diluted compositions should comprise adiluent containing from 0.1 to 10 wt. percent of an emulsifier and from0.1 to 5 wt. percent of the dimedone derivative. The preferredemulsifier is a mixture of polyoxyethylene ethers of mixed partial oleicesters of sorbitol anhydrides available from Sigma Chemical Co. underthe trade name Tween and otherwise known as Polysorbate 80." Thismaterial is commonly used as an emulsifying agent in the preparation ofpharmaceuticals. The use in pharmaceutical formulations is discussed inJowdy, Carolina J. Pharm, 33, 465, 467 1952). Other suitable emulsifiersinclude: sodium lauryl sulfate and earboxymethyllcellulose.

The compounds of this invention have general antimicrobial activity.They are effective against staphylococcus au reus, pseudomonasaeruginosa, streptococcus faecalis, escherichia coli, etc. The compoundsalso have fungicidal activity. They are, for example, somewhat effectiveagainst Mucor Genevensis, Rhizopus Stolonifer, Saccharomyces Cerevisiae,and Candida Albicans.

The invention will be more fully understood by reference to thefollowing examples which are set fort herein. solelyfor the purpose ofillustration. 4

EXAMPLE I 5.6 grams (0.04 moles) of dimedone (5,5-dimethyl-1,3-cyclohexanedione) and 30 milliliters of 50 percent methanol-waterare placed into a 50 milliliter flask fitted with a heater and refluxcondenser. Mild heat is applied to dissolve and then 0.01 moles ofglutaraldehyde are added. The mixture is heated at reflux for 15minutes, during which time the reaction product forms and partiallyprecipitataes due to its insoluble nature. The reaction mixture iscooled in ice for approximately 20 minutes and subjected to a suctionfilter with a Buchner funnel to obtain the product. Yields are quitehigh because of the insolubility of the product in the reaction solvent.The product is washed in a filter several times with warm 50 percentmethanol water and air-dried or dried in a vacuum desiccator. Theproduct has a melt ing point within the range of 222 to 224C.

EXAMPLE I] 5.6 grams (0.04 moles) of dimedone and 30 milliliters of 50%methanol-water are placed in a 50 milliliter flask fitted with a heaterand reflux condenser. 0.01 moles of succinaldehyde are added. Themixture is heated at reflux for 15 minutes. The dimedone derivative ofsuccinaldehyde is insoluble in the solvent and thus partiallyprecipitates from solution even at the reflux temperatures. The reactionmixture is then cooled in ice for approximately 20 minutes and suctionfilter CH CH3 is applied with a Buchner funnel to obtain the product.Yields are high because of the insolubility of the product in thereaction solvent. The product is then washed in a filter several timeswith warm 50 percent methanol-water and air-dried or dried in a vacuumdesiccator.

EXAMPLE III 5.6 grams (0.04 moles of dimedone and 30 milliliters of 50percent methanolwater are placed in a 50 milliliter flask fitted with aheater and reflux condenser. 0.01 moles of malonalde hyde are added tothe solution. The mixture is heated'at reflux for approximately minutes,during which time the derivative is formed. The derivative is insolublein the solvent and thus partially precipitates even at refluxtemperatures. The reaction mixture is'cooled in ice for minutes andsuction filtration is performed with a Buchner funnel to obtainthe'product. As with the glutaraldehyde and succinald ehyde derivatives,yields are quite high because of the insolubility of the product in areaction solvent. The product is washed in the filter several times with50 percent methanol-water a'nd'air-dried or dried in a vacuumdesiccator.

. EXAMPLE IV The dimedone derivative of glutaraldehyde prepared inaccordance with Example I is compared with phenol and hexachlorophenewith respect to antimicrobial activity by the phenol coefficient test.The phenol coefficient test comprises determining the dilution factor ofan aqueous phenolsolution that is sufficient to kill themicrobe'within'ten minutes but not sufficient to kill it within fiveminutes contact time. The same dilution factor.is determined withrespect tohexachlorophcne and the'dimedone derivative. The dilutionfactor of the dimedoneor hexachlorophene. is thenv divided by thedilution factor of the phenol to give the phenol coefficicut. Theresults of the test are shown as follows in Table- 4 EXAMPLE v Thecompound prepared as described in Example I is tested as a fungicideusing the phenoltest. The results are shown in Table 2.

Table 2 Fungicidal Activity Phenol Organism Class Coefficient MucorGcncvensis Bread Mould 1 0.l3 Rhi/upus Stolonifcr fungus ().l3Saccharomyces ercvisiac Yeast 0.08 Candida Albicans 0. 10

Yeast Pathogen While the invention has been described by means ofseveral specific examples, it is'to be understood that modifications andvariations of the invention,- obvious to those skilled in the art, maybe made without departing from the spirit and scope of the invention.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

l. The compound of the formula:

where x is an integer from 2 to 4.

2. A compound defined in claim 1 wherein x is 2. 3. A compound definedin claim 1 wherein x is 3.

4. A compound defined in claim 1 wherein x is 4.

1. THE COMPOUND OF THE FORMULA:
 2. A compound defined in claim 1 whereinx is
 2. 3. A compound defined in claim 1 wherein x is
 3. 4. A compounddefined in claim 1 wherein x is 4.